Genotype risk score of common susceptible variants for prediction of type 2 diabetes mellitus in Japanese: the Shimanami Health Promoting Program (J-SHIPP study). Development of type 2 diabetes mellitus and genotype risk score.

Recent genomewide association studies have successfully identified several genotypes susceptible to type 2 diabetes mellitus (T2DM). However, only a few studies have investigated whether these variations confer a risk of the future development of T2DM. We conducted a longitudinal genetic epidemiological study to clarify the prognostic significance of the T2DM-associated variants. The sample population consisted of 2037 middle-aged to elderly community residents. Personal health records were obtained from a clinical database administered by the local government. Genotype risk score was calculated by the following variants, namely, KCNQ1, TCF7L2, CDKAL1, HHEX, IGF2BP2, CDKN2AB, SLC30A8, KCNJ11, PPARG, and GCKR. Susceptibility of these variants in Japanese has been confirmed by association analysis. Among the 1824 subjects who did not have T2DM at baseline, 95 cases of T2DM were newly diagnosed during the 9.4-year follow-up period. Mean genotype risk score in these subjects was significantly higher than that in the subjects who remained nondiabetic (9.5 ± 1.8 vs 9.1 ± 2.0, P = .042). Although the initial mean body mass index (24.7 ± 3.2 vs 23.0 ± 2.8, P < .001) and initial glucose (106 ± 18 vs 90 ± 13, P < .001) were also significantly higher in those subjects who developed T2DM, the genotype risk score remained an independent determinant of the development of T2DM even after adjustment for these parameters and possible confounding factors. Per-allele odds ratio for the development of T2DM was 1.12 (95% confidence interval, 1.00-1.25; P = .049). Type 2 diabetes mellitus-susceptible genetic variants identified by a cross-sectional genomewide association study were significantly associated with the future development of T2DM in a general population sample.